This invention relates to novel compounds, and their derivatives, which are useful in therapy and to processes for their preparation. It also relates to intermediates used in the preparation of such compounds and derivatives, compositions containing them and their uses.
Endometriosis is a common gynaecological disease that affects 10-20% women of reproductive age and manifests itself in the presence of functional ectopic endometrial glands and stroma at locations outside the uterine cavity {Prentice, A. (2001). Bmj 323, 93-95.}. Patients with endometriosis may present with many different symptoms and severity. Most commonly this is dysmenorrhoea, but chronic pelvic pain, dyspareunia, dyschexia, menorrhagia, lower abdominal or back pain, infertility, bloating and pain on micturition are also part of the constellation of symptoms of endometriosis.
Originally described by Von Rokitansky in 1860 {Von Rokitansky, C. (1860). Ztsch K K Gesellsch der Aerzte zu Wien 37, 577-581.}, the exact pathogenesis of endometriosis is unclear {Witz, C. A. (1999). Clinical Obstetrics & Gynaecology 42, 566-585.; Witz, C. A. (2002). Gynaecologic & Obstetric Investigation 53, 52-62.}, but the most widely accepted theory is the implantation, or Sampson, theory {Sampson, J. A. (1927). American Journal of Obstetrics & Gynaecology 14, 422-429.}. The Sampson theory proposes that the development of endometriosis is a consequence of retrograde dissemination and implantation of andometrial tissue into the peritoneal cavity during menstruation. Following attachment, the fragments of endometrium recruit a vascular supply and undergo cycles of proliferation and shedding under local and systemic hormonal controls. In women with patent fallopian tubes, retrograde menstruation appears to be a universal phenomenon {Liu, D. T. (Hitchcock, A.). British Journal of Obstetrics & Gynaecology 93, 859-862.}. The disease often manifests itself as rectovaginal endometriosis or adenomyosis, ovarian cystic endometriomas and, most commonly, peritoneal endometriosis. The major sites of attachment and lesion growth within the pelvis are the ovaries, broad and round ligaments, fallopian tubes, cervix, vagina, peritoneum and the pouch of Douglas. At its most severe, endometriosis can cause profound structural modification to peritoneal cavity, including multi-organ adhesions and fibrosis.
Symptomatic endometriosis can be managed medically and surgically, where the intention is to remove the ectopic lesion tissue. Surgical intervention can be either conservative, aiming to preserve the reproductive potential of the patient, or comparatively radical for severe disease, involving dissection of the urinary tract, bowel, and rectovaginal septum, or total abdominal hysterectomy and bilateral salpingo-oopherectomy. Medical pharmacological treatments such as the androgenic therapies, danazol and gestrinone, the constellation of GnRH agonists, buserelin, goserelin, leuprolide, nafarelin and triptorelin, GnRH antagonists, cetrorelix and abarelix, as well as the progestogens, including medroxyprogesterone acetate, induce lesion atrophy by suppressing the production of estrogen. These approaches are not without unwanted side effects; danazol and gestrinone include weight gain, hirsuitism, acne, mood changes and metabolic effects on the cardiovascular system. The group of GnRH agonists and antagonists are found to cause a profound suppression of estrogen leading to vasomotor effects (hot flashes) and depletion of bone mineral density, which restricts their use to only six months of therapy. The group of progestogens, including medroxyprogesterone acetate, suppress the gonadotropins, but do not down-regulate ovarian estrogen production to the same extent as the GnRH analogues. The side effects include irregular bleeding, bloating, weight gain and metabolic effects on the cardiovascular system.
Uterine leiomyomas {Flake, G. P., et al. (2003). Environmental Health Perspectives 111, 1037-1054.; Walker, C. L. (2002). Recent Progress in Hormone Research 57, 277-294.}, or fibroids, are the most common benign tumours found in women and occur in the majority of women by the time they reach the menopause. Although uterine fibroids are the most frequent indication for hysterectomy in the United States, as with endometriosis, remarkably little is known about the underlying pathophysiology of the disease. As with endometriotic lesions, the presence of enlarged uterine fibroids is associated with abnormal uterine bleeding, dysmenorrhoea, pelvic pain and infertility. Outside of surgical management, medical treatments commonly used for endometriosis, such as GnRH analogues or danazol, have been shown to suppress fibroid growth by inducing a reversible hypoestrogenic state {Chrisp, P., and Goa, K. L. (1990). Drugs 39, 523-551.; Chrisp, P., and Goa, K. L. (1991). Drugs 41, 254-288.; De Leo, V., et al. (2002). Drug Safety 25, 759-779.; Ishihara, H., et al. (2003). Fertility & Sterility 79, 735-742.}. However, the future disease management of both uterine fibroids and endometriosis will rely on the development of more effective, well-tolerated and safer agents than those that are currently available.
Steroidal progestins (i.e., progesterone receptor agonists) are commonly used in women's health, such as in contraception and hormone therapy and for the treatment of gynecological disorders. Recent studies in women and in nonhuman primates also indicate that progesterone receptor antagonists may have potential applications in contraception and for the treatment of reproductive disorders such as fibroids and endometriosis. Currently, all clinically available progesterone receptor agonists and antagonists are steroidal compounds. They often cause various side effects due to their functional interactions with other steroid receptors or because of effects associated with their steroidal metabolites {Winneker, Richard C. et al.; Endocrinology and Reproductive Disorders Division, Women's Health Research Institute, Collegeville, Pa., USA. Seminars in Reproductive Medicine (2005), 23(1), 46-57}.
Progesterone receptor antagonists [anti-progestins (APs)], including the founding members of the class mifepristone (RU-486; Roussel UCLAF, Romainville, France), onapristone (ZK 98 299; Schering AG), ZK 137 316 and ZK-230 211 as well as CDB-4453 and CDB-4124 (Progenta, BIOQUAL Inc), are compounds that bind to the progesterone receptor (PR) and prevent progesterone-induced gene expression {Spitz, I. M. (2003). Steroids 68, 981-993.}. Acting on the estrogen primed endometrium, progesterone plays an essential role in the differentiation and ductal morphogenesis of endometrial tissue, but also participates in the inhibition of myometrial contractility and the polarisation of leukocyte Th1/Th2 responses that are critical for embryo implantation and the maintenance of pregnancy. A number of studies have investigated the potential beneficial effects of anti-progestins on the signs and symptoms of endometriosis {Grow, D. R., et al. (1996). Journal of Clinical Endocrinology & Metabolism 81, 1933-1939.; Kettel, L. M., et al. (1996). Fertility & Sterility 65, 23-28.; Kettel, L. M., et al. (1998). American Journal of Obstetrics & Gynaecology 178, 1151-1156. }and uterine fibroids {Eisinger, S. H., et al. (2003). Obstetrics & Gynaecology 101, 243-250.; Murphy, A. A., and Castellano, P. Z. (1994). Current Opinion in Obstetrics & Gynaecology 6, 269-278.; Murphy, A. A., et al. (1995). Fertility & Sterility 63, 761-766.; Steinauer, J., Pritts, et al. (2004). Obstetrics & Gynaecology 103, 1331-1336.; Yang, Y., et al. (1996). Chinese. Chung-Hua Fu Chan Ko Tsa Chih [Chinese Journal of Obstetrics & Gynaecology] 31, 624-626.}. Unlike GnRH analogues, and other conventional pharmacological approaches, anti-progestins, especially mifepristone, appear to be able to reduce lesion or fibroid volume, whilst maintaining a tonic level of ovarian oestrogen secretion. Such anti-progestins induce amenorrhoea and endometrial compaction, and also appear to sufficiently protect against rapid oestrogen-dependent bone loss {Grow, D. R., et al. (1996). Journal of Clinical Endocrinology & Metabolism 81, 1933-1939.}. In contrast GnRH analogues cause a rapid loss in bone mineral density, a clinical feature which limits their treatment duration to 6 months. Whilst mifepristone is a potent anti-progestin, it also has equipotent anti-glucocorticoid activity. Outside of a palliative treatment of hypercortisolism for Cushing's syndrome {Chu, J. W., et al. (2001). J Clin Endocrinol Metab 86, 3568-3573.; Sartor, O., and Cutler, G. B., Jr. (1996). Clin Obstet Gynaecol 39, 506-510.; Spitz, I. M. (2003). Steroids 68, 981-993.; Van Look, P. F., and von Hertzen, H. (1995). Human Reproduction Update 1: 19-34.}, the anti-glucocorticoid activity is an undesirable feature of mifepristone and potentially many of the steroidal classes of anti-progestins.
A further class of steroidal and non-steroidal compounds, termed the progesterone receptor modulators (PRMs, or mesoprogestins), including asoprisnil (J867, benzaldehyde, 4-[(11β, 17β)-17-methoxy-17-(methoxymethyl)-3-oxoestra-4,9-dien-11-yl]-, 1-oxime; Jenpharm, TAP), J912, J956, J1042, have also been described. In addition to their potential utility in hormone replacement and as contraceptives, these classes of compounds could be considered to have utility in the treatment of endometriosis and uterine leiomyoma {Chwalisz, K., et al. (2004). Semin Reprod Med 22, 113-119.; Chwalisz, K., et al. (2002). Annals of the New York Academy of Sciences 955, 373-388; discussion 389-393.; DeManno, D., et al. (2003). Steroids 68, 1019-1032.}. Asoprisnil and structurally-related PRMs differ from anti-progestins and progestins in animal models, demonstrating partial progestogenic activity in the rabbit endometrium (McPhail's test {McPhail, M. K. (1934). Journal of physiology 83, 145-156.}) and guinea pig vagina, for instance. Pre-clinical studies with asoprisinil in primates have indicated that PRMs suppress endometrial growth and, unlike the effects of progestins, endometrial ER and PR expression is not repressed {Chwalisz, K., et al. (2000). Steroids 65, 741-751.; DeManno, D., et al. (2003). Steroids 68, 1019-1032.; Elger, W., et al. (2000). Steroids 65, 713-723.}.
The compounds of the present invention have been found to have useful pharmaceutical properties. They may be used to treat endometriosis, uterine fibroids (leiomyomata) and menorrhagia, adenomyosis, primary and secondary dysmenorrhoea (including symptoms of dyspareunia, dyschexia and chronic pelvic pain), chronic pelvic pain syndrome, precocious puberty, cervical ripening, contraception (emergency), breast carcinoma, ovarian carcinoma, endometrial carcinoma, prostate carcinoma, pulmonary carcinoma, testicular carcinoma, gastric carcinoma, meningioma, anxiety, premenstrual syndrome, premenstrual dysphoric disorder, alcohol abuse and reward, or Charcot-Marie-Tooth disease.
Particularly of interest are the following diseases or disorders: endometriosis, uterine fibroids (leiomyomata), menorrhagia, adenomyosis, primary and secondary dysmenorrhoea (including symptoms of dyspareunia, dyschexia and chronic pelvic pain), and chronic pelvic pain syndrome.
In particular, the compounds and derivatives of the present invention exhibit activity as progesterone receptor antagonists and may be useful for treatment where progesterone receptor antagonism is indicated.
More particularly, the compounds and derivatives of the present invention may be useful for treating endometriosis and/or uterine fibroids (leiomyomata).
International Patent Application WO 2002/085860 describes pyrazole derivatives of the formula:
wherein R1, R2, R3 and R4 are as defined therein, which are modulators of HIV reverse transcriptase.
According to the present invention there is provided a compound of the formula (I),
or a pharmaceutically acceptable derivative thereof, wherein:                R1 represents H, C1-6alkyl, C1-6alkyloxy, C3-8cycloalkyl, or halo;        R2 represents H, C1-6alkyl (optionally substituted by R3), phenyl (optionally substituted by CN), or Het;                    R3 represents OH, CN, Het, —R4—C1-6alkyl, or CONR5R6;                            R4 represents —CO2—, or —O—;                R5 and R6 independently represent H, C1-6alkyl (optionally substituted by OR7) or C3-8cycloalkyl;                                    R7 represents H or C1-6alkyl;                                                Het represents a five or six membered aromatic heterocyclic group containing (i) from one to four nitrogen heteroatom(s) or (ii) one or two nitrogen heteroatom(s) and one oxygen or one sulphur heteroatom or (iii) one or two oxygen or sulphur heteroatom(s), said heterocyclic group being optionally substituted by one or more groups selected from CN and C1-6alkyl;                                                R8 represents C1-6alkyl, C1-6alkyloxy, C3-8cycloalkyl, or halo;        R9 and R10 independently represent H, C1-6alkyl, C1-6alkyloxy, CN, CF3 or halo.        
In the above definitions alkyl groups containing the requisite number of carbon atoms, except where indicated, can be unbranched or branched chain. Examples include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkyloxy include methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, sec-butyloxy and t-butyloxy. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term halogen means fluoro, chloro, bromo or iodo.
Heterocycles included within the definition of “heterocycle” are pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl and quinoxalinyl, together with partially or fully saturated versions thereof as well as azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, oxazepanyl, and morpholinyl.
Preferably R1 represents C3-8cycloalkyl, and more preferably it represents cyclopropyl. Preferably R2 represents C1-6alkyl, more preferably it represents C1-6alkyl substituted with R3. Preferably R3 represents CONR5R6. Preferably R4 represents O. Preferably R5 represents H. Preferably R6 represents C1-6alkyl, more preferably it represents methyl. Preferably R8 represents C3-8cycloalkyl, more preferably it represents cyclopropyl. Preferably R9 represents H or halo, more preferably it represents H. Preferably R10 represents H or halo, more preferably it represents H.
The above described embodiments of the invention may be combined with one or more further embodiments such that further embodiments are provided wherein two or more variables are defined more specifically in combination. For example, within the scope of the invention is a further embodiment wherein the variables R1, R2, R3, R4, R5, R6, R8, R9, and R10 all have the more limited definitions assigned to them in the more specific embodiments described above. All such combinations of the more specific embodiments described and defined above are within the scope of the invention
Preferred compounds according to the present invention are:    4-[(3,5-Dimethyl-1H-pyrazol-4-yl)oxy]benzonitrile;    4-(5-Cyclopropyl-3-methyl-1H-pyrazol-4-yloxy)-2,6-dimethyl-benzonitrile;    4-(5-cyclopropyl-3-methyl-1H-pyrazol-4-yloxy)-2-methyl-benzonitrile;    4-[(3,5-Dicyclopropyl-1H-pyrazol-4-yl)oxy]-2,6-dimethylbenzonitrile;    4-(3,5-Diethyl-1H-pyrazol-4-yloxy)-benzonitrile;    4-(3,5-Dimethyl-1H-pyrazol-4-yloxy)-2,6-dimethyl-benzonitrile;    4-(3,5-Dicyclopropyl-1H-pyrazol-4-yloxy)-benzonitrile;    4-(3,5-Diethyl-1H-pyrazol-4-yloxy)-2,6-dimethyl-benzonitrile;    4-(3,5-Diethyl-1H-pyrazol-4-yloxy)-2-methoxy-benzonitrile;    4-(3-Cyclopropyl-5-methyl-1H-pyrazol-4-yloxy)-benzonitrile;    4-(3,5-Diethyl-1H-pyrazol-4-yloxy)-phthalonitrile;    4-(3,5-Diethyl-1H-pyrazol-4-yloxy)-2-trifluoromethyl-benzonitrile;    4-(3,5-Dicyclopropyl-1H-pyrazol-4-yloxy)-2-methyl-benzonitrile;    2-Chloro-4-(3,5-dicyclopropyl-1H-pyrazol-4-yloxy)-benzonitrile;    4-[(5-Ethyl-3-methoxy-1H-pyrazol-4-yl)oxy]benzonitrile;    4-[(3-Cyclopropyl-1H-pyrazol-4-yl)oxy]-2,6-dimethylbenzonitrile;    4-{[1-(2-Hydroxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl]oxy}benzonitrile;    2-Fluoro-4-[1-(2-hydroxy-ethyl)-3,5-dimethyl-1H-pyrazol-4-yloxy]-benzonitrile;    2-Chloro-4-[1-(2-hydroxy-ethyl)-3,5-dimethyl-1H-pyrazol-4-yloxy]-benzonitrile;    4-[1-(2-Hydroxy-ethyl)-3,5-dimethyl-1H-pyrazol-4-yloxy]-phthalonitrile;    4-[3,5-Diethyl-1-(2-hydroxy-ethyl)-1H-pyrazol-4-yloxy]-benzonitrile;    4-[3,5-Diethyl-1-(2-hydroxy-ethyl)-1H-pyrazol-4-yloxy]-2-fluoro-benzonitrile;    2-Chloro-4-[1-(2-hydroxy-ethyl)-3,5-diethyl-1H-pyrazol-4-yloxy]-benzonitrile;    4-[3,5-Diethyl-1-(2-hydroxy-ethyl)-1H-pyrazol-4-yloxy]-2-methyl-benzonitrile;    4-[3,5-Diethyl-1′-(2-hydroxy-ethyl)-1H-pyrazol-4-yloxy]-phthalonitrile;    4-[3,5-Diethyl-1-(2-hydroxy-ethyl)-1H-pyrazol-4-yloxy]-2-methoxy-benzonitrile;    4-[3,5-Diethyl-1-(2-hydroxy-ethyl)-1H-pyrazol-4-yloxy]-2,6-dimethyl-benzonitrile;    4-{[3,5-Dicyclopropyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile;    4-{[3-Cyclopropyl-1-(2-hydroxyethyl)-5-methyl-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile;    4-{[5-cyclopropyl-1-(2-hydroxyethyl)-3-methyl-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile;    4-{[3,5-Diethyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile;    Ethyl[4-(4-cyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]acetate;    Ethyl[4-(4-cyano-3,5-dimethylphenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]acetate;    Ethyl[4-(4-cyano-3,5-dimethyl-phenoxy)-3,5-dimethyl-pyrazol-1-yl]acetate;    Ethyl[4-(4-cyanophenoxy)-3,5-dicyclopropyl-pyrazol-1-yl]acetate;    Ethyl[4-(4-cyano-3,5-dimethyl-phenoxy)-3,5-diethyl-pyrazol-1-yl]acetate;    Ethyl[4-(4-cyano-3-trifluoromethyl-phenoxy)-3,5-dicyclopropyl-pyrazol-1-yl]acetate;    Ethyl[4-(4-cyano-3-methyl-phenoxy)-3,5-dicyclopropyl-pyrazol-1-yl]acetate;    Ethyl[4-(4-cyano-3,5-dimethyl-phenoxy)-3-cyclopropyl-pyrazol-1-yl]acetate;    Ethyl[4-(3-chloro-4-cyano-phenoxy)-3,5-dicyclopropyl-pyrazol-1-yl]acetate;    Ethyl[4-(4-cyanophenoxy)-3-cyclopropyl-5-methyl-pyrazol-1-yl]acetate;    Ethyl[4-(4-cyanophenoxy)-5-cyclopropyl-3-methyl-pyrazol-1-yl]acetate;    Ethyl[4-(4-cyano-3-methyl-phenoxy)-3-cyclopropyl-5-methyl-pyrazol-1-yl]acetate;    Ethyl[4-(4-cyano-3-methyl-phenoxy)-5-cyclopropyl-3-methyl-pyrazol-1-yl]acetate;    Ethyl[4-(4-cyano-3,5-dimethylphenoxy)-3-cyclopropyl-5-methyl-1H-pyrazol-1-yl]acetate;    Ethyl[4-(4-cyano-3,5-dimethylphenoxy)-5-cyclopropyl-3-methyl-1H-pyrazol-1-yl]acetate;    Ethyl 2-[4-(4-cyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]-2-methylpropanoate;    Methyl 2-[4-(4-cyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]-2-methylpropanoate;    2-[4-(4-Cyano-3,5-dimethylphenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methyl-acetamide;    2-[4-(4-Cyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]-N-methyl-acetamide;    2-[4-(4-Cyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]-acetamide;    2-[4-(4-Cyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]-N-(hydroxyethyl)-acetamide;    2-[4-(4-Cyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]-N-(methoxyethyl)-acetamide;    2-[4-(4-Cyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]-N,N-dimethyl-acetamide;    2-[4-(4-Cyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]-N-ethyl-acetamide;    2-[4-(4-Cyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]-N-cyclopropyl-acetamide;    2-[4-(4-Cyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]-N-isopropyl-acetamide;    2-[4-(4-Cyano-3,5-dimethyl-phenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-acetamide;    2-[4-(4-Cyano-3,5-dimethyl-phenoxy)-3,5-dimethyl-1H-pyrazol-1-yl]-N-methyl-acetamide;    2-[4-(4-Cyano-3,5-dimethyl-phenoxy)-3,5-dimethyl-1H-pyrazol-1-yl]-acetamide;    2-[4-(4-Cyanophenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-acetamide;    2-[4-(4-Cyanophenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methyl-acetamide;    2-[4-(4-Cyano-3,5-dimethyl-phenoxy)-3,5-diethyl-1H-pyrazol-1-yl]-N-methyl-acetamide;    2-[4-(4-Cyano-3,5-dimethyl-phenoxy)-3,5-diethyl-1H-pyrazol-1-yl]-acetamide;    2-[4-(4-Cyano-3-trifluoromethyl-phenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methyl-acetamide;    2-[4-(4-Cyano-3-methyl-phenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methyl-acetamide;    2-[4-(4-Cyano-3,5-dimethyl-phenoxy)-5-cyclopropyl-3-methyl-1H-pyrazol-1-yl]-N-methyl-acetamide;    2-[4-(4-Cyano-3,5-dimethyl-phenoxy)-3-cyclopropyl-5-methyl-1H-pyrazol-1-yl]-N-methyl-acetamide;    2-[4-(4-Cyano-3,5-dimethyl-phenoxy)-3-cyclopropyl-5-methyl-1H-pyrazol-1-yl]-acetamide;    2-[4-(4-Cyano-3,5-dimethyl-phenoxy)-5-cyclopropyl-3-methyl-1H-pyrazol-1-yl]-acetamide;    2-[4-(4-Cyano-dimethyl-phenoxy)-3-cyclopropyl-1H-pyrazol-1-yl]-N-methyl-acetamide;    2-[4-(4-Cyanophenoxy)-5-cyclopropyl-3-methyl-1H-pyrazol-1-yl]-N-methyl-acetamide;    2-[4-(4-Cyanophenoxy)-3-cyclopropyl-5-methyl-1H-pyrazol-1-yl]-N-methyl-acetamide;    2-[4-(4-Cyano-3-methyl-phenoxy)-3-cyclopropyl-5-methyl-1H-pyrazol-1-yl]-N-methyl-acetamide;    2-[4-(4-Cyano-3-methyl-phenoxy)-5-cyclopropyl-3-methyl-1H-pyrazol-1-yl]-N-methyl-acetamide;    2-[4-(3-Chloro-4-cyanophenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methyl-acetamide;    2-[4-(4-Cyanophenoxy)-5-ethyl-3-methoxy-1H-pyrazol-1-yl]-acetamide;    2-[4-(4-Cyano-3,5-dimethyl-phenoxy)-3-cyclopropyl-pyrazol-1-yl]-2-methyl-propanamide;    2-[4-(4-Cyanophenoxy)-3,5-diethyl-pyrazol-1-yl]-2-methyl-N-methyl-propanamide;    2-[4-(4-Cyano-3,5-dimethyl-phenoxy)-5-chloro-3-cyclopropyl-1H-pyrazol-1-yl]-N-methyl-acetamide;    2-[4-(4-Cyano-3,5-dimethyl-phenoxy)-3-chloro-5-cyclopropyl-1H-pyrazol-1-yl]-N-methyl-acetamide;    4-{[1-(Cyanomethyl)-3,5-dimethyl-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile;    4-{[1-(Cyanomethyl)-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile;    4-{[1-(Cyanomethyl)-3,5-diethyl-1H-pyrazol-4-yl]oxy}benzonitrile;    4-{[1-(Cyanomethyl)-3,5-diethyl-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile;    4-{[1-(Cyanomethyl)-5-ethyl-3-methoxy-1H-pyrazol-4-yl]oxy}benzonitrile;    4-{[1-(1-Cyano-1-methylethyl)-3-cyclopropyl-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile;    4-{1-(1-Cyano-1-methylethyl)-3,5-dimethyl-1H-pyrazol-4-yl]oxy}-2,6-dimethyl-benzonitrile;    4-{1-(1-Cyano-1-methylethyl)-3,5-ethyl-1H-pyrazol-4-yl]oxy}-benzonitrile;    4-{1-(1-Cyano-ethyl)-3,5-ethyl-1H-pyrazol-4-yl]oxy}-benzonitrile;    4-({3-Cyclopropyl-5-methyl-1-[(5-methylisoxazol-3-yl)methyl]-1H-pyrazol-4-yl}oxy)-2,6-dimethyl benzonitrile;    4-({5-Cyclopropyl-3-methyl-1-[(5-methylisoxazol-3-yl)methyl]-1H-pyrazol-4-yl}oxy)-2,6-dimethyl benzonitrile;    4-({5-Cyclopropyl-3-methyl-1-[(isoxazol-3-yl)methyl]-1H-pyrazol-4-yl}oxy)-2,6-dimethylbenzonitrile;    4-({3-Cyclopropyl-5-methyl-1-[(isoxazol-3-yl)methyl]-1H-pyrazol-4-yl}oxy)-2,6-dimethylbenzonitrile;    4-({5-Cyclopropyl-3-methyl-1-[(isoxazol-3-yl)methyl]-1H-pyrazol-4-yl}oxy)-benzonitrile;    4-({3-Cyclopropyl-5-methyl-1-[(isoxazol-3-yl)methyl]-1H-pyrazol-4-yl}oxy)-benzonitrile;    4-{[5-Ethyl-1-(1H-imidazol-2-ylmethyl)-3-methyl-1H-pyrazol-4-yl]oxy}-benzonitrile;    4-({3,5-Dicyclopropyl-1-[(pyrimidin-5-yl)methyl]-1H-pyrazol-4-yl}oxy)-2,6-dimethylbenzonitrile;    4-({3,5-Diethyl-1-[(isoxazol-3-yl)methyl]-1H-pyrazol-4-yl}oxy)-benzonitrile;    4-({3,5-Diethyl-1-[(5-methylisoxazol-3-yl)methyl]-1H-pyrazol-4-yl}oxy)-benzonitrile;    4-({3,5-Diethyl-1-[(3,5-dimethylisoxazol-4-yl)methyl]-1H-pyrazol-4-yl}oxy)-benzonitrile;    4-({3,5-Diethyl-1-[(pyridin-2-yl)methyl]-1H-pyrazol-4-yl}oxy)-benzonitrile;    4-({3,5-Diethyl-1-[(1-methylimidazol-2-yl)methyl]-1H-pyrazol-4-yl}oxy)-benzonitrile;    4-({3,5-Diethyl-1-[(thiazol-5-yl)methyl]-1H-pyrazol-4-yl}oxy)-benzonitrile;    4-({3,5-Diethyl-1-[(pyridin-4-yl)methyl]-1H-pyrazol-4-yl}oxy)-benzonitrile;    4-({3,5-Diethyl-1-[(pyridin-3-yl)methyl]-1H-pyrazol-4-yl}oxy)-benzonitrile;    4-({3,5-Diethyl-1-[(pyrimidin-5-yl)methyl]-1H-pyrazol-4-yl}oxy)-benzonitrile;    4-({3,5-Dicyclopropyl-1-[(isoxazol-3-yl)methyl]-1H-pyrazol-4-yl}oxy)-benzonitrile;    4-{[3-Cyclopropyl-5-methyl-1-(4H-1,2,4-triazol-3-ylmethyl)-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile;    4-{[3,5-Diethyl-1-(4H-1,2,4-triazol-3-ylmethyl)-1H-pyrazol-4-yl]oxy}benzonitrile;    4-({3,5-Diethyl-1-[(5-methyl-4H-1,2,4-triazol-3-yl)methyl]-1H-pyrazol-4-yl}oxy)benzonitrile;    4-({3,5-Diethyl-1-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]-1H-pyrazol-4-yl}oxy)benzonitrile;    4-({3,5-Diethyl-1-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-1H-pyrazol-4-yl}oxy)benzonitrile;    4-{[3,5-Diethyl-1-(1,3,4-thiadiazol-2-ylmethyl)-1H-pyrazol-4-yl]oxy}benzonitrile;    4-{[3,5-Dicyclopropyl-1-(1H-pyrazol-3-ylmethyl)-1H-pyrazol-4-yl]oxy}benzonitrile;    4-{[3-Cyclopropyl-5-methyl-1-(1H-1,2,3-triazol-5-ylmethyl)-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile;    4-[(3,5-Diethyl-1-methyl-1H-pyrazol-4-yl)oxy]benzonitrile;    4-[(3,5-Diethyl-1-propyl-1H-pyrazol-4-yl)oxy]benzonitrile;    4-[(3,5-Diethyl-1-ethyl-1H-pyrazol-4-yl)oxy]benzonitrile;    4-[(3,5-Diethyl-1-phenyl-1H-pyrazol-4-yl)oxy]benzonitrile;    4-[4-(4-Cyanophenoxy)-3,5-diethyl-1H-pyrazol-1-yl]benzonitrile;    4-[(3,5-Dicyclopropyl-1-pyridin-3-yl-1H-pyrazol-4-yl)oxy]-2,6-dimethylbenzonitrile;    4-[(3,5-Dicyclopropyl-1-pyrimidin-5-yl-1H-pyrazol-4-yl)oxy]-2,6-dimethylbenzonitrile;    4-[(3,5-Diethyl-1′H-1,4′-bipyrazol-4-yl)oxy]benzonitrile;and the pharmaceutically acceptable salts and solvates thereof.
Particularly preferred compounds according to the present invention include:    4-{[3,5-Dicyclopropyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile;    2-[4-(4-Cyano-3,5-dimethylphenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methylacetamide;    2-[4-(4-Cyano-3,5-dimethyl-phenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-acetamide;    2-[4-(4-Cyanophenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methyl-acetamide;    2-[4-(4-Cyano-3-methyl-phenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methyl-acetamide;    2-[4-(3-Chloro-4-cyanophenoxy)-3,5-dicyclopropyl-1H-pyrazol-1-yl]-N-methyl-acetamide;    4-{[1-(Cyanomethyl)-3,5-diethyl-1H-pyrazol-4-yl]oxy}benzonitrile;    4-{[1-(Cyanomethyl)-3,5-diethyl-1H-pyrazol-4-yl]oxy}-2,6-dimethylbenzonitrile;    4-({3,5-Dicyclopropyl-1-[(pyrimidin-5-yl)methyl]-1H-pyrazol-4-yl}oxy)-2,6-dimethylbenzonitrile;    4-({3,5-Diethyl-1-[(isoxazol-3-yl)methyl]-1H-pyrazol-4-yl}oxy)-benzonitrile;and the pharmaceutically acceptable salts and solvates thereof.
Pharmaceutically acceptable derivatives of the compounds of formula (I) according to the invention include salts, solvates, complexes, polymorphs and crystal habits thereof, prodrugs, stereoisomers, geometric isomers, tautomeric forms, and isotopic variations of compounds of formula (I). Preferably, pharmaceutically acceptable derivatives of compounds of formula (I) comprise salts, solvates, esters and amides of the compounds of formula (I). More preferably, pharmaceutically acceptable derivatives of compounds of formula (I) are salts and solvates.
The pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition and base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.
Suitable base salts are formed from bases that form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, 2002).
Pharmaceutically acceptable salts of compounds of formula I may be prepared by one or more of three methods:    (i) by reacting the compound of formula (I) with the desired acid or base;    (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula (I) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or    (iii) by converting one salt of the compound of formula (I) to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.
All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term ‘amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order (‘glass transition’). The term ‘crystalline’ refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order (‘melting point’).
The compounds of the invention may also exist in unsolvated and solvated forms. The term ‘solvate’ is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term ‘hydrate’ is employed when said solvent is water.
A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates—see “Polymorphism in Pharmaceutical Solids” by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.
When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
Also included within the scope of the invention are multi-component complexes (other than salts and solvates) wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt. Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together—see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004). For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975).
The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as ‘thermotropic’ and that resulting from the addition of a second component, such as water or another solvent, is described as ‘lyotropic’. Compounds that have the potential to form lyotropic mesophases are described as ‘amphiphilic’ and consist of molecules which possess an ionic (such as —COO−Na+, —COO−K+, or —SO3−Na+) or non-ionic (such as —N−N+(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshome and A. Stuart, 4th Edition (Edward Arnold, 1970).
Hereinafter all references to compounds of formula (I) include references to salts, solvates, multi-component complexes and liquid crystals thereof and to solvates, multi-component complexes and liquid crystals of salts thereof.
As indicated above, so-called ‘prodrugs’ of the compounds of formula (I) are also within the scope of the invention. Thus certain derivatives of compounds of formula (I), which may have little or no pharmacological activity themselves, can be converted into compounds of formula I having the desired activity, for example by hydrolytic cleavage, when administered into, or onto, the body. Such derivatives are referred to as ‘prodrugs’. Further information on the use of prodrugs may be found in “Pro-drugs as Novel Delivery Systems”, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).
Prodrugs in accordance with the invention can be produced by replacing appropriate functionalities present in the compounds of formula (I) with certain moieties known to those skilled in the art as ‘pro-moieties’ as described, for example, in “Design of Prodrugs” by H. Bundgaard (Elsevier, 1985).
Some examples of prodrugs in accordance with the invention include    (i) where the compound of formula (I) contains an alcohol functionality (—OH), an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of formula (I) is replaced by (C1-C6)alkanoyloxymethyl; and    (ii) where the compound of formula (I) contains a primary or secondary amino functionality (—NH2 or —NHR where R≠H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of formula (I) is/are replaced by (C1-C10)alkanoyl.
Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.
Moreover, certain compounds of formula (I) may themselves act as prodrugs of other compounds of formula (I).
Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula (I) contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (‘tautomerism’) can occur. This can take the form of proton tautomerism in compounds of formula (I) containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism. Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula I, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counter ion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.
Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture. When any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art—see, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel and S. H. Wilen (Wiley, 1994).
The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulphur, such as 35S.
Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO.
The compounds of formula (I) should be assessed for their biopharmaceutical properties, such as solubility and solution stability (across pH), permeability, etc., in order to select the most appropriate dosage form and route of administration for treatment of the proposed indication.
Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
The compounds of the invention may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof).
The compounds of the present invention may be administered in combination with COX inhibitors. Thus in a further aspect of the invention, there is provided a pharmaceutical product containing a progesterone receptor antagonist and one or more COX inhibitors as a combined preparation for simultaneous, separate or sequential use in the treatment of endometriosis. COX inhibitors useful for combining with the compounds of the present invention include, but are not limited to:    (i) ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, prapoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, diclofenac, fenclofenec, alclofenac, ibufenac, isoxepac, furofenac, tiopinac, zidometacin, acetyl salicylic acid, indometacin, piroxicam, tenoxicam, nabumetone, ketorolac, azapropazone, mefenamic acid, tolfenamic acid, diflunisal, podophyllotoxin derivatives, acemetacin, droxicam, floctafenine, oxyphenbutazone, phenylbutazone, proglumetacin, acemetacin, fentiazac, clidanac, oxipinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flufenisal, sudoxicam, etodolac, piprofen, salicylic acid, choline magnesium trisalicylate, salicylate, benorylate, fentiazac, clopinac, feprazone, isoxicam and 2-fluoro-a-methyl[1,1′-biphenyl]-4-acetic acid, 4-(nitrooxy)butyl ester (See Wenk, et al., Europ. J. Pharmacol. 453:319-324 (2002));    (ii) meloxicam, (CAS registry number 71125-38-7; described in U.S. Pat. No. 4,233,299), or a pharmaceutically acceptable salt or prodrug thereof;    (iii) celecoxib (U.S. Pat. No. 5,466,823), valdecoxib (U.S. Pat. No. 5,633,272), deracoxib (U.S. Pat. No. 5,521,207), rofecoxib (U.S. Pat. No. 5,474,995), etoricoxib (International Patent Application Publication No. WO 98/03484), JTE-522 (Japanese Patent Application Publication No. 9052882), or a pharmaceutically acceptable salt or prodrug thereof;    (iv) Parecoxib (described in U.S. Pat. No. 5,932,598), which is a therapeutically effective prodrug of the tricyclic Cox-2 selective inhibitor valdecoxib (described in U.S. Pat. No. 5,633,272), in particular sodium parecoxib;    (v) ABT-963 (described in International Patent Application Publication No. WO 00/24719)    (vi) Nimesulide (described in U.S. Pat. No. 3,840,597), flosulide (discussed in J. Carter, Exp. Opin. Ther. Patents. 8(1), 21-29 (1997)), NS-398 (disclosed in U.S. Pat. No. 4,885,367), SD 8381 (described in U.S. Pat. No. 6,034,256), BMS-347070 (described in U.S. Pat. No. 6,180,651), S-2474 (described in European Patent Publication No. 595546) and MK-966 (described in U.S. Pat. No. 5,968,974);    (vii) darbufelone (Pfizer), CS-502 (Sankyo), LAS 34475 (Almirall Profesfarma), LAS 34555 (Almirall Profesfarma), S-33516 (Servier), SD 8381 (Pharmacia, described in U.S. Pat. No. 6,034,256), BMS-347070 (Bristol Myers Squibb, described in U.S. Pat. No. 6,180,651), MK-966 (Merck), L-783003 (Merck), T-614 (Toyama), D-1367 (Chiroscience), L-748731 (Merck), CT3 (Atlantic Pharmaceutical), CGP-28238 (Novartis), BF-389 (Biofor/Scherer), GR-253035 (Glaxo Wellcome), 6-dioxo-9H-purin-8-yl-cinnamic acid (Glaxo Wellcome), and S-2474 (Shionogi).
The compounds of the present invention may be administered in combination with PDE5 inhibitors. Thus in a further aspect of the invention, there is provided a pharmaceutical product containing a progesterone receptor antagonist and one or more PDEV inhibitors as a combined preparation for simultaneous, separate or sequential use in the treatment of endometriosis.
PDEV inhibitors useful for combining with compounds of the present invention include, but are not limited to:
                (i) Preferably 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil, e.g. as sold as Viagra®) also known as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulphonyl]-4-methylpiperazine (see EP-A-0463756);5-(2-ethoxy-5-morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see EP-A-0526004); 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-n-propoxy phenyl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrmidin-7-one (see WO 98/49166); 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO99/54333); (+)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1 (R)-methylethoxy) pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, also known as 3-ethyl-5-{5-[4-ethylpiperazin-1-ylsulphonyl]-2-([(1R)-2-methoxy-1-methylethyl]oxy)pyridin-3-yl}-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO99/54333); 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxy ethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, also known as 1-{6-ethoxy-5-[3-ethyl-6,7-dihydro-2-(2-methoxyethyl)-7-oxo-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridylsulphonyl}-4-ethylpiperazine (see WO 01/27113, Example 8); 5-[2-iso-Butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(1-methylpiperidin-4-yl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO 01/27113, Example 15); 5-[2-Ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO 01/27113, Example 66); 5-(5-Acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO 01/27112, Example 124); 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (see WO 01/27112, Example 132); (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl) pyrazino[2′,1′: 6,1]pyrido[3,4-b]indole-1,4-dione (tadalafil, IC-351, Cialis®), i.e. the compound of examples 78 and 95 of published international application WO95/19978, as well as the compound of examples 1, 3, 7 and 8; 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil, LEVITRA®) also known as 1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f]-as-triazin-2-yl)-4-ethoxyphenyl]sulphonyl]-4-ethylpiperazine, i.e. the compound of examples 20, 19, 337 and 336 of published international application WO99/24433; the compound of example 11 of published international application WO93/07124 (EISAI); compounds 3 and 14 from Rotella D P, J. Med. Chem., 2000, 43, 1257; 4-(4-chlorobenzyl)amino-6,7,8-trimethoxyquinazoline; N-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-yl)-4-propxyphenyl]sulfonyl]-1-methyl-2-pyrrolidine propanamide [“DA-8159” (Example 68 of WO00/27848)]; and 7,8-dihydro-8-oxo-6-[2-propoxyphenyl]-1H-imidazo[4,5g]quinazoline and 1-[3-[1-[(4-fluorophenyl)methyl]-7,8-dihydro-8-oxo-1H-imidazo[4,5-g]quinazolin-6-yl]-4-propoxyphenyl]carboxamide; 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl) pyrimidine-5-carboxamide (TA-1790); 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzene sulfonamide (DA 8159) and pharmaceutically acceptable salts thereof.            (ii) 4-bromo-5-(pyridylmethylamino)-6-[3-(4-chlorophenyl)-propoxy]-3(2H)pyridazinone; 1-[4-[(1,3-benzodioxol-5-ylmethyl)amiono]-6-chloro-2-quinozolinyl]-4-piperidine-carboxylic acid, mono-sodium salt; (+)-cis-5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-methyl-cyclopent-4,5]imidazo[2,1-b]purin-4(3H)one; furazlocillin; cis-2-hexyl-5-methyl-3,4,5,6a,7,8, 9,9a-octahydrocyclopent[4,5]-imidazo[2,1-b]purin-4-one; 3-acetyl-1-(2-chlorobenzyl)-2-propyl indole-6-carboxylate; 3-acetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate; 4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-chlorophenyl) propoxy)-3-(2H)pyridazinone; l-methyl-5(5-morpholinoacetyl-2-n-propoxyphenyl)-3-n-propyl-1,6-dihydro- 7H-pyrazolo(4,3-d)pyrimidin-7-one; 1-[4-[(1,3-benzodioxol-5-ylmethyl)amino]-6-chloro-2-quinazolinyl]-4-piperidinecarboxylic acid, monosodium salt; Pharmaprojects No. 4516 (Glaxo Wellcome); Pharmaprojects No. 5051 (Bayer); Pharmaprojects No. 5064 (Kyowa Hakko; see WO 96/26940); Pharmaprojects No. 5069 (Schering Plough); GF-196960 (Glaxo Wellcome); E-8010 and E-4010 (Eisai); Bay-38-3045 & 38-9456 (Bayer); FR229934 and FR226807 (Fujisawa); and Sch-51866.
Preferably the PDEV inhibitor is selected from sildenafil, tadalafil, vardenafil, DA-8159 and 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one. Most preferably the PDE5 inhibitor is sildenafil and pharmaceutically acceptable salts thereof. Sildenafil citrate is a preferred salt.
The compounds of the present invention may be administered in combination with a V1a antagonist. Thus, in a further aspect of the invention, there is provided a pharmaceutical product containing a progesterone receptor antagonist and one or more V1a antagonists as a combined preparation for simultaneous, separate or sequential use in the treatment of endometriosis.
A suitable vasopressin V1a receptor antagonist is, for example, (4-[4-Benzyl-5-(4-methoxy-piperidin-1-ylmethyl)-4H-[1,2,4]triazol-3-yl]-3,4,5,6-tetrahydro-2H[1,2′]bipyridinyl), which is Example 26 in WO 2004/37809. A further example of a suitable vasopressin V1a receptor antagonist is 8-chloro-5-Methyl-1-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-5,6-dihydro-4H-2,3,5,10b-tetraazo-benzo[e]azulene, or a pharmaceutically acceptable salt or solvate thereof, which is Example 5 in WO 04/074291.
Further examples of vasopressin V1a receptor antagonists for use with the invention are: SR49049 (Relcovaptan), atosiban (Tractocile®), conivaptan (YM-087), VPA-985, CL-385004, Vasotocin and OPC21268. Additionally, the V1a receptor antagonists described in WO 01/58880 are suitable for use in the invention.
The compounds of the present invention may be administered in combination with an alpha adrenergic receptor antagonist (also known as α-adrenoceptor blocker, α-receptor blocker or α-blocker). Thus, in a further aspect of the invention, there is provided a pharmaceutical product containing a progesterone receptor antagonist and one or more alpha adrenergic receptor antagonists as a combined preparation for simultaneous, separate or sequential use in the treatment of endometriosis.
α1-Adrenergic receptor antagonists useful for the present invention include, but are not limited to, terazosin (U.S. Pat. No. 4,026,894), doxazosin (U.S. Pat. No. 4,188,390), prazosin (U.S. Pat. No. 3,511,836), bunazosin (U.S. Pat. No. 3,920,636), alfuzosin (U.S. Pat. No. 4,315,007), naftopidil (U.S. Pat. No. 3,997,666), tamsulosin (U.S. Pat. No. 4,703,063), silodosin (U.S. Pat. No. 5,387,603), phentolamine and phentolamine mesylate (U.S. Pat. No. 2,503,059), trazodone (U.S. Pat. No. 3,381,009), indoramin (U.S. Pat. No. 3,527,761), phenoxybenzamine (U.S. Pat. No. 2,599,000), rauwolfa alkaloids (natural product from the shrub Rauwolfia serpentine), Recordati 15/2739 (WO 93/17007), SNAP 1069 (WO 94/08040 e.g. 3, compound 9, page 77 & table 3, page 86), SNAP 5089 (WO 94/10989), RS17053 (U.S. Pat. No. 5,436,264), SL 89.0591 (EP 435749), and abanoquil (EP 100200); the compounds disclosed in International Application Publication No. WO 03/076427 in particular 5-cyclopropyl-7-methoxy-2-(2-morpholin-4-ylmethyl-7,8-dihydro[1,6]-naphthyridin-6(5H)-yl)-4(3H)-quinazolinone (example 11), and the compounds disclosed in International Application Publication No. WO 98/30560 in particular 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (example 19); and pharmaceutically acceptable derivatives thereof. Preferred α-adrenergic receptor antagonists are doxazosin, 5-cyclopropyl-7-methoxy-2-(2-morpholin-4-ylmethyl-7,8-dihydro[1,6]-naphthyridin-6(5H)-yl)-4(3H)-quinazolinone and 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline and pharmaceutically acceptable derivatives thereof. The mesylate salt of 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline is of particular interest (see WO 01/64672).
α2-Adrenergic receptor antagonists suitable for the present invention include dibenamine (DE 824208), tolazoline (U.S. Pat. No. 2,161,938), trimazosin (U.S. Pat. No. 3,669,968), efaroxan (EP 71368), yohimbine (M R Goldberg et al, Pharmacol. Rev. 35, 143-180 (1987)), idazoxan (EP 33655), and clonidine (U.S. Pat. No. 3,202,660);
Non-selective α-adrenergic receptor antagonists suitable for the present invention include dapiprazole (U.S. Pat. No. 4,252,721);
The compounds of the present invention may be administered in combination with an 5-alpha reductase inhibitor. Thus, in a further aspect of the invention, there is provided a pharmaceutical product containing a progesterone receptor antagonist and one or more 5-alpha reductase inhibitors as a combined preparation for simultaneous, separate or sequential use in the treatment of endometriosis.
5-alpha reductase inhibitors include inhibitors of 5-alpha reductase isoenzyme 2. Suitable compounds for use in the present invention are PROSCAR® (also known as finasteride, U.S. Pat. Nos. 4,377,584 and 4,760,071), compounds described in WO 93/23420, EP0572166, WO 93/23050, WO 93/23038, WO 93/23048, WO 93/23041, WO 93/23040, WO 93/23039, WO 93/23376, WO 93/23419, EP0572165, and WO 93/23051.
The compounds of the present invention may be administered in combination with an agent which lowers estrogen levels, or which antagonises the estrogen receptor. Thus, in a further aspect of the invention, there is provided a pharmaceutical product containing a progesterone receptor antagonist and one or more agents which lower estrogen levels, or antagonise the estrogen receptor, as a combined preparation for simultaneous, separate or sequential use in the treatment of endometriosis.
Agents which lower estrogen levels include gonadotropin releasing hormone (GnRH) agonists, GnRH antagonists and estrogen synthesis inhibitors. Agents which antagonise the estrogen receptor, i.e. estrogen receptor antagonists, include anti-estrogens.
GnRH agonists suitable for the present invention include leuprorelin (Prostap-Wyeth), buserelin (Suprefact-Shire), goserelin (Zoladex-Astra Zeneca), triptorelin (De-capeptyl-Ipsen), narfarelin (Synarel-Searle), deslorelin (Somagard-Shire), and histrelin/supprelin (Ortho Pharmaceutical Corp/Shire).
GnRH antagonists suitable for the present invention include teverelix (also known as antarelix), abarelix (Plenaxis-Praecis Pharmaceuticals Inc.), cetrorelix (Cetrotide-ASTA Medica), and ganirelix (Orgalutran-Organon).
Anti-estrogens suitable for the present invention include tamoxifen, Faslodex (Astra Zeneca), idoxifene (see Coombes et al. (1995) Cancer Res. 55, 1070-1074), raloxifene or EM-652 (Labrie, F et al, (2001) J steroid Biochem Mol Biol, 79, 213). Estrogen synthesis inhibitors suitable for the present invention include aromatase inhibitors. Examples of aromatase inhibitors include Formestane (4-OH androstenedione), Exemestane, Anastrozole (Arimidex) and Letroxole.
The compounds of the present invention may be administered in combination with an alpha-2-delta ligand. Thus, in a further aspect of the invention, there is provided a pharmaceutical product containing a progesterone receptor antagonist and one ore more alpha-2-delta ligands, as a combined preparation for simultaneous, separate or sequential use in the treatment of endometriosis.
Examples of alpha-2-delta ligands for use in the present invention are those compounds, or pharmaceutically acceptable salts thereof, generally or specifically disclosed in U.S. Pat. No. 4,024,175, particularly gabapentin, EP641330, particularly pregabalin, U.S. Pat. No. 5,563,175, WO-A-97/33858, WO-A-97/33859, WO-A-99/31057, WO-A-99/31074, WO-A-97/29101, WO-A-02/085839, particularly [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, WO-A-99/31075, particularly 3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one and C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, WO-A-99/21824, particularly (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, WO-A-01/90052, WO-A-01/28978, particularly (1α,3α,5α)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, EP0641330, WO-A-98/17627, WO-A-00/76958, particularly (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, WO-A-03/082807, particularly (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid and (3S,5R)-3-amino-5-methyl-octanoic acid, WO-A-2004/039367, particularly (2S,4S)-4-(3-fluoro-phenoxymethyl)-pyrrolidine-2-carboxylic acid, (2S,4S)-4-(2,3-difluoro-benzyl)-pyrrolidine-2-carboxylic acid, (2S,4S)-4-(3-chlorophenoxy)proline and (2S,4S)-4-(3-fluorobenzyl)proline, EP1178034, EP1201240, WO-A-99/31074, WO-A-03/000642, WO-A-02/22568, WO-A-02/30871, WO-A-02/30881 WO-A-2/100392, WO-A-02/100347, WO-A-02/42414, WO-A-02/32736 and WO-A-02/28881, all of which are incorporated herein by reference.
Preferred alpha-2-delta ligands for use in the combination of the present invention include: gabapentin, pregabalin, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetc acid, (1α,3α,5α)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl -octanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline and (2S,4S)-4-(3-fluorobenzyl)proline or pharmaceutically acceptable salts thereof.
Further preferred alpha-2-delta ligands for use in the combination of the present invention are (3S,5R)-3-amino-5-methyloctanoic acid, (3S,5R)-3-amino-5-methylnonanoic acid, (3R,4R,5R)-3-amino-4,5-dimethylheptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyloctanoic acid, and the pharmaceutically acceptable salts thereof.
Particularly preferred alpha-2-delta ligands for use in the combination of the present invention are selected from gabapentin, pregabalin, (1α,3α,5α)(3-amino-methyl-bicyclo[3.2.0]hept-3-yl)-acetic acid, (2S,4S)-4-(3-chlorophenoxy)proline and (2S,4S)-4-(3-fluorobenzyl)proline or pharmaceutically acceptable salts thereof.
The compounds of the present invention may be administered in combination with an oxytocin receptor antagonist. Thus, in a further aspect of the invention, there is provided a pharmaceutical product containing a progesterone receptor antagonist and one ore more oxytocin antagonists, as a combined preparation for simultaneous, separate or sequential use in the treatment of endometriosis.
Examples of oxytocin receptor antagonists suitable for the present invention are atosiban (Ferring AB), barusiban (Ferring AB), TT-235 (Northwestern University), and AS-602305 (Serono SA).
The contents of the published patent applications mentioned above, and in particular the general formulae of the therapeutically active compounds of the claims and exemplified compounds therein, are incorporated herein in their entirety by reference thereto.
The compounds of the present invention may also be administered in combination with any one or more of the following    (i) Aromatase inhibitor;    (ii) Estrogen receptor agonist;    (iii) Angiogenesis inhibitor;    (iv) VEGF inhibitor;    (v) Kinase inhibitor;    (vi) Protein farnesyl transferase inhibitor;    (vii) Androgen receptor modulator;    (viii) Androgen receptor agonists;    (ix) Androgen receptor antagonists;    (x) Prostanoid receptor agonist;    (xi) Prostanoid receptor antagonist;    (xi) Prostaglandin synthetase inhibitor;    (xii) Bioflavanoid;    (xiii) Alkylating agent;    (xiv) Microtobule modulator, e.g. Microtobule stabilizer;    (xv) Topoisomerase I inhibitor;    (xvi) Metalloprotease inhibitor; or    (xvii) Progesterone modulator.
Thus, in a further aspect of the invention, there is provided a pharmaceutical product containing a progesterone receptor antagonist and any one or more of the following    (i) Aromatase inhibitor;    (ii) Estrogen receptor agonist;    (iii) Angiogenesis inhibitor;    (iv) VEGF inhibitor;    (v) Kinase inhibitor;    (vi) Protein farnesyl transferase inhibitor;    (vii) Androgen receptor modulator;    (viii) Androgen receptor agonists;    (ix) Androgen receptor antagonists;    (x) Prostanoid receptor agonist;    (xi) Prostanoid receptor antagonist;    (xi) Prostaglandin synthetase inhibitor;    (xii) Bioflavanoid;    (xiii) Alkylating agent;    (xiv) Microtobule modulator, e.g. Microtobule stabilizer;    (xv) Topoisomerase I inhibitor;    (xvi) Metalloprotease inhibitor; or    (xvii) Progesterone modulator,as a combined preparation for simultaneous, separate or sequential use in the treatment of endometriosis.
Generally, compounds of the invention will be administered as a formulation in association with one or more pharmaceutically acceptable excipients. The term ‘excipient’ is used herein to describe any ingredient other than the compound(s) of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
Pharmaceutical compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in “Remington's Pharmaceutical Sciences”, 19th Edition (Mack Publishing Company, 1995).
The compounds of the invention may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.
Formulations suitable for oral administration include solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particulates, liquids, or powders; lozenges (including liquid-filled); chews; gels; fast dispersing dosage forms; films; ovules; sprays; and buccavmucoadhesive patches.
Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (made, for example, from gelatin or hydroxypropylmethylcellulose) and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
The compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001).
For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate. Generally, the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.
Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting. The final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
The formulation of tablets is discussed in “Pharmaceutical Dosage Forms: Tablets”, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).
Consumable oral films are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (I), a film-forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity-modifying agent and a solvent. Some components of the formulation may perform more than one function.
The film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
Other possible ingredients include anti-oxidants, colorants, flavourings and flavour enhancers, preservatives, salivary stimulating agents, cooling agents, co-solvents (including oils), emollients, bulking agents, anti-foaming agents, surfactants and taste-masking agents.
Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.
Solid formulations for oral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.
Suitable modified release formulations for the purposes of the invention are described in U.S. Pat. No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in “Pharmaceutical Technology On-line”, 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.
The compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
The preparation of parenteral formulations under sterile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
The solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the invention may be formulated as a suspension or as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions comprising drug-loaded poly(dl-lactic-coglycolic) acid (PGLA) microspheres.
The compounds of the invention may also be administered topically, (intra)dermally, or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated—see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject™, Bioject™, etc.) injection.
Formulations for topical administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactc acid.
Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 μg to 20 mg of the compound of the invention per actuation and the actuation volume may vary from 1 μl to 100 μl. A typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol. Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, PGLA. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
The compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.
The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
Drug-cyclodextrin complexes, for example, are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
It is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound in accordance with the invention, may conveniently be combined in the form of a kit suitable for coadministration of the compositions.
Thus the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
The kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory aid.
For administration to human patients, the total daily dose of the compounds of the invention is typically in the range <1 mg to 1000 mg depending, of course, on the mode of administration. For example, oral administration may require a total daily dose of from <1 mg to 1000 mg, while an intravenous dose may only require from <1 mg to 500 mg. The total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein.
These dosages are based on an average human subject having a weight of about 60 kg to 70 kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
As used herein, the terms “treating” and “to treat”, mean to alleviate symptoms, eliminate the causation either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms. The term “treatment” includes alleviation, elimination of causation (either on a temporary or permanent basis) of, or prevention of symptoms and disorders associated with endometriosis and/or uterine leiomyoma. The treatment may be a pre-treatment as well as a treatment at the on-set of symptoms.
The compounds of the present invention may be tested in the screens set out below:
1.0 In vitro Functional Assay for Progesterone Receptor (PR) Antagonism
The assay for PR antagonism takes advantage of the extensively reported modulation of alkaline phosphatase (AP) expression in human breast T47D mammary carcinoma cells {Beck et al., D. P. (1993). The progesterone antagonist RU486 acquires agonist activity upon stimulation of cAMP signalling pathways. Proc Natl Acad Sci USA 90, 4441-4445; Fensome et al. (2002). New progesterone receptor antagonists: 3,3-disubstituted-5-aryloxindoles. Bioorg Med Chem Left 12, 3487-3490; Zhang et al., (2002a). 6-Aryl-1,4-dihydro-benzo d 1,3 oxazin-2-ones: a novel class of potent, selective, and orally active nonsteroidal progesterone receptor antagonists. Journal of Medicinal Chemistry 45, 4379-4382; Zhang et al., (2003). Novel 6-aryl-1,4-dihydrobenzo d oxazine-2-thiones as potent, selective, and orally active nonsteroidal progesterone receptor agonists. Bioorganic & Medicinal Chemistry Letters 13, 1313-1316; Zhang et al., (2002b). Potent nonsteroidal progesterone receptor agonists: synthesis and SAR study of 6-aryl benzoxazines. Bioorganic & Medicinal Chemistry Letters 12, 787-790; Zhang, Z. et al., (2000). In vitro characterization of trimegestone: a new potent and selective progestin. Steroids 65, 637-643.}. In the presence of progesterone, endogenous AP expression is induced in T47D cells and is inhibited by compounds possessing PR antagonistic activity. In the absence of progesterone any agonist activity is also observed as an induction of AP activity. By running the assay in two formats (+/−progesterone (P4)), compounds behaving as PR antagonists, agonists or partials can be identified.
The materials required to grow T47D cells and perform the progesterone-induced AP assay are outlined in Table 1.
TABLE 1Assay media (agonist format): DMEM without phenol red + 5%CS-FCS + 2 mM Glutamax.Assay media (antagonist format): DMEM without phenol red + 5%CS-FCS + 2 mM Glutamax + 10 nM P4.CatalogueReagentSuppliernumberT47D human mammaryAmerican tissueHTB-133carcinoma cellsculture collections;http://www.atcc.org/Dimethyl sulphoxide (DMSO)SigmaD2650Dulbecco's modified Eagle's MediumGibco21969-035(DMEM)DMEM without phenol redGibco31053-028L-Glutamax, 200 mMGibco35050-038Charcoal stripped foetal calf serum (CS-GlobepharmFCS)Phosphate buffered saline (PBS)Gibco14190-094Foetal bovine serum (FBS)SigmaF-7524BD Great EscAPe SEAPFisherK2041-1Chemiluminescence Detection kitProgesterone (P4)SigmaP-6149Pluronic-F127Molecular ProbesP6867RU486 (Mifepristone)SigmaM-8046
Briefly, T47D cells are grown by propagating in DMEM+10% FBS+2 mM Glutamax at 37° C./5% CO2. At 80-90% confluence, the media is exchanged for phenol red free DMEM+5% CS-FCS (Assay media) and cultured for a further 24 hrs at 37° C./5% CO2. T47D cells are then plated at 2.5×104 cells/well in 100 μL assay media in sufficient 96 well plates for the assay, in triplicates of each condition. For example, for a 5 point IC50 curve on one compound, this is equivalent to 36 wells (2×18 wells, ±P4). These plates are then cultured for 24 hrs at 37° C./5% CO2, leaving the outside wells blank by the addition of 200 μL PBS.
A 10 mM stock solution of compounds is prepared in DMSO (stored −20° C. in 10 □L aliquots). A 10 mM DMSO stock of RU486 is used as a standard pure PR antagonist. The compounds under investigation are added to assay medium, or a mixture of 0.05% pluronic acid in PBS, ±10 nM P4 to give a final concentration of 20 □M (i.e. 10 □L of the 10 mM stock to 5 □L assay medium ±10 nM P4). The samples are mixed thoroughly and serial dilutions of compounds from 10 □M to 0.1 nM in a 96 well plate, are prepared as follows:
The outside wells are left blank. Assay medium (225 μL) is added to one half of the plate (−P4), rows 3-8, and to the other half of the plate, assay medium +10 nM P4. To row 2, 250 μL of the top concentration of compound (20 μM±10 nM P4) is added. 25 μL of the 20 mM stock from row 2 is removed and added to the 225 μL of assay medium ±10 nM P4 in row 3 and thoroughly mixed. This process is repeated down the plate to row 7 to achieve serial dilutions. The vehicle control is adjusted to contain 0.1% DMSO (i.e. 20 μL to 10 mL assay medium ±10 nM P4 to give a concentration of 0.2% DMSO, add 250 μL to row 8).
100 μL of reagent from the dilution plates are transferred into the corresponding wells containing T47D cells in 100 μL assay medium, to give a final concentration of 10 μM to 0.1 nM compound (5 nM P4 antagonist format). The cells for 20 hrs at 37° C./5% CO2., then media is removed, cells washed with PBS (200 μL) and lysed by placing the cells at −80° C. for 15 min and thawing at room temp. The Freeze-thaw lysis is repeated, then PBS (50 μL) is added to each well. After 5 min, 30 μL of CSPD chemiluminescent substrate solution (final 0.06125 mM, 1.25 mM substrate solution x 20 dilution with chemiluminescent enhancer, Great EscAPe SEAP Chemiluminescence Detection kit) is added to each well and mixed. The plates are incubated for 30 mins at room temperature and luminescence measured on a luminometer (VICTOR, Wallac).
The assay is performed in triplicate, in the agonist format (no exogenous P4), sigmoid fitting of the results is expressed as alkaline phosphatase induction (luminescence, arbitrary units or % with maximal progesterone response as 100%) by the test compounds. In this format, the EC50 value is defined as the drug concentration required to produce a 50% induction of AP activity compared with 5 nM alone. Compounds with agonism, or partial agonism, that is an induction of AP activity which is sub-maximal to that induced by P4, are discarded in this way. In the antagonist format (5 nM P4), curve fitting the results is expressed as alkaline phosphatase inhibition by the test compounds. In this format, the IC50 value is defined as the drug concentration required to produce a 50% inhibition of AP activity compared with 5 nM alone. For the purposes of compounds exemplified here, the IC50 values are less than 5 μM. In a preferred embodiment, the IC50 value is less than 500 nM. In a more preferred embodiment, the IC50 is less than 50 nM.
2.0 In vitro Functional Assay for Glucocorticoid Activity (GR)
A SW1353 cell line, stably transfected with a full length GR construct and mouse mammary tumour virus (MMTV)-luciferase (Luc) reporter is used to perform the in vitro functional assay for glucocorticoid activity in this assay. The materials required to grow SW1353-MMTV-GR-Luc cells and perform the assay are indicated below, or outlined in Table 1.
SW1353-MMTV-GR-Luc cells, grown in DMEM containing 10% FBS, 2 mM glutamax and G418 (0.5 mg/mL, Gibco cat no.10131-027), are plated at 0.5×104 cells/well (384 well black issue culture clear bottom plates (Greiner cat no. 781091)) in 30 μL using a Multidrop micro and are incubated at 37° C., 5% CO2 overnight. The culture media is replaced with assay media (30 μL; DMEM-phenol red containing 1 mg/L insulin, 2 g/L lactalbumin hydrolysate and ascorbate (0.5 mg/L), added just prior to use) for at least 4 hrs prior to dosing. The assay is performed in two formats, an antagonist format in which test compounds are assessed for their ability to block the effect of 20 nM dexamethasone on luciferase activity, and an agonist format. A separate 384 plate is used to assess compounds in both formats.
A Genesis robot is used to dilute and stamp out ½ log unit (11 point) dose responses (starting at 1 μM final; 16 compounds/384 well plate) from a 96 well plate containing 4 mM stock concentrations of compounds to be tested. The compounds under investigation are diluted in to assay medium +3.75% DMSO, or a mixture of 0.05% pluronic acid in PBS. A dexamethasone and RU-486 (1 μM final) positive control are prepared from concentrated stocks. A MATRIX Platemate is used to transfer 10 μL of diluted compounds to plates and either 10 μL of media or standards, so that the final volume of the assay is 50 μL. The cells and compounds are incubated at 37° C., 5% CO2 overnight. The Steady-Glo LuciLite reagent (Promega cat no. E2520) is then re-constituted and 30 μL added per well, left in the dark for 5 mins and then the plate is read on a Wallac luminescence counter. All data points are measured in duplicate
In the agonist format, sigmoid fitting of the results, expressed as luciferase induction (% of maximal dexamethasone response) by the test compounds, is achieved and EC50 value is determined. In the antagonist format, results are expressed as luciferase inhibition by the test compounds and an IC50 value is determined.
3.0 In vivo Assessment for Progesterone Receptor Antagonism Using the McPhail's Assay
The classical quantitative assessment of progestogenic activity is the McPhail's assay, performed in the immature rabbit (McPhail, 1934).
According to the present invention there is also provided a process for the production of a compound of formula (I), which comprises:    (i) the condensation of a compound of formula (II) with a compound of formula (V), or a salt or hydrate thereof, optionally in the presence of an acid or a base:
    (ii) the condensation of a compound of formula (VI) with a compound of formula (V), or a salt or hydrate thereof, optionally in the presence of an acid or a base:
    (iii) the condensation of a compound of formula (VII), with a compound of formula (V), or a salt or hydrate thereof, optionally in the presence of an acid or a base:
     wherein R1, R2, R8, R9 and R10 are as previously defined, and L1 and L2, respectively, are each suitable leaving groups; preferably —N(C1-C6 alkyl)2, more preferably —N(CH3)2.
Also within the scope of the invention are intermediate compounds of formula (II), (VI) and (VII) as hereinbefore defined, all salts, solvates and complexes thereof and all solvates and complexes of salts thereof as defined hereinbefore for compounds of formula (I). The invention includes all polymorphs of the aforementioned species and crystal habits thereof.
When preparing compounds of formula (I) in accordance with the invention, it is open to a person skilled in the art to routinely select the form of compound of formula (II), (VI) and (VII) that provides the best combination of features for this purpose. Such features include the melting point, solubility, processability and yield of the intermediate form and the resulting ease with which the product may be purified on isolation.
The compounds of the invention may have the advantage that they are more potent, have a longer duration of action, have a broader range of activity, are more stable, have fewer side effects or are more selective, or have other more useful properties than the compounds of the prior art.
Thus the invention provides:                (i) a compound of formula (I) or a pharmaceutically acceptable derivative thereof;        (ii) a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable derivative thereof;        (iii) a pharmaceutical formulation including a compound of formula (I) or a pharmaceutically acceptable derivative thereof, together with a pharmaceutically acceptable excipients, diluent or carrier;        (iv) a compound of formula (I) or a pharmaceutically acceptable derivative or composition thereof, for use as a medicament;        (v) the use of a compound of formula (I) or of a pharmaceutically acceptable derivative or composition thereof, for the manufacture of a medicament for the treatment of endometriosis, uterine fibroids (leiomyomata), menorrhagia, adenomyosis, primary and secondary dysmenorrhoea (including symptoms of dyspareunia, dyschexia and chronic pelvic pain), chronic pelvic pain syndrome;        (vi) use as in (v) where the disease or disorder is endometriosis and/or uterine fibroids (leiomyomata);        (vii) a method of treatment of a mammal to treat endometriosis, uterine fibroids (leiomyomata), menorrhagia, adenomyosis, primary and secondary dysmenorrhoea (including symptoms of dyspareunia, dyschexia and chronic pelvic pain), chronic pelvic pain syndrome including treating said mammal with an effective amount of a compound of formula (I) or with a pharmaceutically acceptable derivative or composition thereof;        (viii) a method as in (vii) where the disease or disorder is endometriosis and/or uterine fibroids (leiomyomata);        (ix) intermediates of the formulae (II), (VI) and (VII);        
All of the compounds according to the formula (I) can be prepared by conventional routes such as the procedures described in the general methods presented below, or by the specific methods described in the Examples section, or by similar methods thereto. The present invention also encompasses any one or more of these processes for preparing the compounds of formula (I), in addition to any novel intermediates used therein.
In the following general methods, R1 to R10 are as previously defined for a compound of formula (I) unless otherwise stated.
In Scheme 1 below, compounds of formula (I) may be prepared by the condensation of a compound of formula (II) with a compound of formula (V):H2NNHR2  (V)or a salt or hydrate thereof, optionally in the presence of an acid or a base. The base is preferably a tertiary amine base, such as triethylamine. The acid is preferably acetic acid. In a typical procedure, a solution of the compound of formula (II) in a suitable solvent, such as ethanol, is treated with the compound of formula (V), or the salt or hydrate thereof, and, if used, the appropriate acid or base, at a temperature of from room temperature to the reflux temperature of the solvent. In a preferred procedure, the reaction mixture is heated under reflux.

Functional equivalents of compounds of formula (II) may also be used in this reaction. These include compounds of formula (VI) or (VII) below, in which L1 and L2, respectively, are each suitable leaving groups; preferably —N(C1-C6 alkyl)2, more preferably —N(CH3)2.

Thus, a compound of formula (I) may be prepared by the condensation of a compound of formula (VI), or (VII), with a compound of formula (V), or a salt or hydrate thereof, optionally in the presence of an acid or a base (the base preferably being a tertiary amine base, such as triethylamine, and the acid preferably being acetic acid). In a typical procedure, a solution of the compound of formula (VI), or (VII), in a suitable solvent (such as ethanol) is treated with the compound of formula (V), or the salt or hydrate thereof, and, if used, the appropriate acid or base, at a temperature of from room temperature to the reflux temperature of the solvent. In a preferred procedure, the reaction mixture is heated under reflux. Compounds of formula (VI), or (VII), are particularly suitable for the synthesis of compounds of formula (I), in which R1, or R8, respectively, represents H.
Compounds of formula (VI) in which R1 is H and L1 is dimethylamino may be prepared by the reaction of a compound of formula (VIII), below, with dimethylformamide dimethylacetal at an elevated temperature, preferably at about 100° C. Compounds of formula (VIII) in which R8 is H and L1 is dimethylamino may be prepared by the reaction of a compound of formula (IX), below, under the same conditions. Other compounds of formula (VI), or (VII), in which L1 or L2 is dimethylamino, may be prepared analogously.

Compounds of formula (VIII) are either commercially available or may be prepared by the reaction of a compound of formula (X):R1COCH2Br  (X)with a compound of formula (XI):
In a typical procedure, a solution of the compound of formula (XI), in a suitable solvent, such as acetone, is treated with a suitable base, such as caesium carbonate, and the compound of formula (X). In a preferred procedure, the reaction mixture is heated, for example under reflux. Optionally, a nucleophilic catalyst, such as sodium iodide or tetrabutylammonium iodide, may be added.
Compounds of formula (IX) are either commercially available or may be prepared from a compound of formula (XII):R8COCH2Br  (XII)and a compound of formula (XI), in the same way that a compound of formula (VIII) may be prepared from a compound of formula (X).
Compounds of formula (II) may be prepared by reaction of a compound of formula (III) with a compound of formula (XI). In a typical procedure, a solution of the compound of formula (III), in a suitable solvent, such as acetone, is treated with a compound of formula (XI) and a suitable base, such as potassium or caesium carbonate, and heated, preferably under reflux. Optionally, a nucleophilic catalyst such as sodium iodide, or tetrabutylammonium iodide, may be added.
Compounds of formula (III) are either commercially available or may be prepared by the reaction of a compound of formula (IV) with a chlorinating reagent. In a typical procedure, a cooled solution of the compound of formula (IV), in a suitable solvent, such as acetonitrile, is treated first with tetrabutylammonium bromide and chlorotrimethylsilane, and then dry dimethylsulphoxide. In another typical procedure, the compound of formula (IV) is treated with sulphuryl chloride, optionally in the presence of a suitable solvent, such as dichloromethane.
It will be appreciated by those skilled in the art that, in many cases, compounds of the formula (I) may be converted into other compounds of the formula (I) by functional group transformations. For instance:                (a) compounds of the formula (I) in which R2 is H may be converted into compounds of the formula (I) in which R2 is optionally substituted C1-C6 alkyl by reaction with an appropriate alkylating agent. In a typical procedure, a solution of a compound of formula (I) in which R2 is H, in a suitable solvent, such as ethanol, acetonitrile or N,N-dimethylformamide, is treated with an alkyl bromide and a base, such as potassium carbonate, sodium ethoxide or sodium hydride, and heated at a temperature of from room temperature to the reflux temperature of the solvent. In a preferred combination the solvent is N,N-dimethylformamide, the base is sodium hydride and the reaction is carried out at room temperature. Examples of alkylating agents include bromoacetonitrile, ethyl bromoacetate, and halomethylheteroaryl reagents. The use of further specific alkylating agents is illustrated in the examples section described below.        (b) compounds of formula (I) in which R2 is H may be converted into compounds of formula (I) in which R2 is a direct linked heteroaryl or substituted phenyl, by reaction with an aryl halide, or heteroaryl halide, under metal catalysed conditions, such as copper iodide and potassium carbonate in toluene containing (1R,2R)-(−)-1,2-bis(methylamino)cyclohexane as catalyst.        (c) compounds of formula (I) in which R2 contains an ester, may be converted into compounds of formula (I) in which R2 contains an amide by aminolysis of the ester with an amine in a suitable solvent such as methanol, ethanol or tetrahydrofuran. Alternatively the ester may be first hydrolysed to the corresponding carboxylic acid, and then converted to an amide using commonly used methods.        (d) compounds of formula (I) in which R2 contains a primary carboxamide may be converted into compounds of formula (I) in which R2 contains a nitrile by dehydration with a suitable dehydrating agent, such as trifluoroacetic anhydride.        
The following Preparations and Examples illustrate the preparation of the compounds of formula (I).
1H Nuclear magnetic resonance (NMR) spectra were in all cases consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million downfield from tetramethylsilane using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.
The following abbreviations have been used throughout:
HRMShigh resolution mass spectrometry;LRMSlow resolution mass spectrometry;hplchigh performance liquid chromatography;nOenuclear Overhauser effect;m.pmelting point;CDCl3deuterochloroform;D6-DMSOdeuterodimethylsulphoxide;CD3ODdeuteromethanol
Where thin layer chromatography (TLC) has been used it refers to silica gel TLC using silica gel 60 F254 plates. “Rf” represents the distance travelled by a compound divided by the distance travelled by the solvent front on a TLC plate.
Where it is stated that compounds were prepared in the manner described for an earlier Preparation or Example, the skilled person will appreciate that reaction times, number of equivalents of reagents and reaction temperatures may be modified for each specific reaction, and that it may nevertheless be necessary or desirable to employ different work-up or purification conditions.